1. Field of the Invention
This invention generally relates to the field of chemotherapeutic agents useful in the inhibition of cytokinesis and cell division for the research and treatment of cancers and other diseases.
2. Description of the Related Art
Highly regulated assembly and disassembly of actin monomers into filaments and bundles (“F-actin”) is the essential basis for cell shape, cytokinesis and motility in eukaryotic cells. Actin filaments build a dynamic intracellular structure in all eukaryotic cells. These filaments as part of the cytoskeleton stabilize the cell and provide a network for unidirectional movement of proteins, which can mediate the localization of other proteins, mRNA or entire organelles. Actin binding proteins are involved in the organization of the actin filament network itself by crosslinking, capping or anchoring these microfilaments to membranes. The most abundant actin binding protein in a cell is actin itself. The actin monomer (ca. 43 kD) has four actin binding sites, which enables it to polymerize into filaments of different size and organization.
Polymerization of actin requires binding of ATP and subsequent hydrolysis into ADP and Pi. This exergonic reaction induces a conformational change in the monomer, exposing actin:actin binding sites. Only a few substances are known to modify the polymerization of actin. These compounds are useful tools to study the coordination and functions of the actin cytoskeleton in the cell.
Inhibiting cytoskeletal dynamics is one of the most powerful strategies employed in cancer treatment. Examples of compounds that bind to actin and inhibit cytoskeletal dynamics include such commonly used cancer drugs such as paclitaxel, eleutherobin, epithilone and discodermalide. However, drugs commonly used for this purpose cause serious side effects on fast-growing cells such as bone marrow cells, hair cells, intestinal brush border cells and germinmal cells, as degradation of these chemicals is slow. This problem is compounded by cumulative cytotoxicity on periferal organs.
The present invention relates to peptides derived by the inventors from sucrose synthase. Sucrose synthase (SuSy) is recognized as an important enzyme of sucrose (Suc) utilization in plant sink tissues. (L. C. Ho., Annu. Rev. Plant Physiol. Plant Mol. Biol. 39 (1988), pp. 355-378). In particular, the highest activity of SuSy often occurs during rapid growth (e.g. elongating maize leaves as described by B. Nguyen-Quoc, et al., Plant Physiol. 94 (1990), pp. 516-523) or during storage product deposition (e.g. developing seeds, as shown by S. S. Sung, et al., Plant Cell Environ. 17 (1994), pp. 419-426). SuSy is a globular protein and thus is generally considered to be soluble in the cytosol. However, some of the enzyme is known to be associated with the plasma membrane, perhaps in a specific complex with glucan synthase(s) in the membrane. Evidence that soluble SuSy binds to both G- and F-actin in vitro, as well as evidence that some of the SuSy may be associated with actin in situ is described in H. Winter, et al., FEBS Letters, Volume 430, Issue 3, 3 Jul. 1998, pages 205-208.
An alternative approach to the use of complex organic molecules to inhibit cell proliferation is the use of synthetic peptides. While other peptides have been shown to cause F-actin bundling in vitro, those peptides are generally highly basic in composition and promote formation of lateral aggregates of F-actin in a rather non-specific manner. In the long run, these compounds offer the prospect of minimalizing side effects by tumor cell-directed transfection of the sequences encoding the drug; in the short run, as peptides are inherently more easily degradable by the organism, they are not expected to cause cumulative cytotoxicity.